One of the manifestations of aging is the accumulation of damage at both cellular and organism levels. Genotoxic stress plays an important role in aging and age-related diseases such as emphysema, which is caused by a failure of lung maintenance and repair after sustained oxidative stress. Cigarette smoke represents a source of oxidants and is considered an environmental hazard that causes pulmonary emphysema. Premature senescence is believed to contribute to genotoxic stress-induced emphysema. The tumor suppressor protein p53 is a key regulator of premature senescence and is activated by the ataxia-telangiectasia mutated (ATM) protein kinase when the ATM inhibitor protein phosphatase 2A (PP2A) dissociates from ATM after genotoxic stress. The mechanism underlying PP2A-C removal from ATM upon genotoxic stress remains totally unexplored. In addition, the role that the ATM/p53 pathway plays in cigarette smoke-induced cellular senescence and the pathogenesis of emphysema remains largely unknown. Here, we plan to test the hypothesis that the lipid raft protein caveolin-1 mediates stress-induced premature senescence by promoting ATM-dependent activation of p53 through sequestration of the ATM inhibitor PP2A-C into caveolae. In addition, it is hypothesized that caveolin-1 plays a central role in oxidant-promoted emphysema in vivo through induction of cellular senescence. This hypothesis will be tested by pursuing three specific aims: Specific Aim 1: Investigate the role of caveolin-1 in PP2A-mediated regulation of ATM function after genotoxic stress. Specific Aim 2: Determine the functional consequences of loss of caveolin-1 expression on ATM-mediated p53 activation and premature senescence. Specific Aim 3: Define the role of caveolin-1 in genotoxic stress-induced pulmonary emphysema in vivo. These studies will provide novel insights into the signaling machinery that links genotoxic stress to cellular senescence and propose caveolin-1 as a novel therapeutic target for the treatment of age-related diseases such as emphysema. PUBLIC HEALTH RELEVANCE: Oxidative stress, including cigarette smoke, promotes premature cellular senescence, which is believed to have an important role in the more complicated aging process, and contributes to age-related diseases like emphysema. The molecular mechanisms underlying cigarette smoke-induced emphysema are not fully understood. Our studies will test the hypothesis that the protein caveolin-1 is a novel regulator of stress-induced cellular senescence and emphysema, and propose caveolin-1 as an alternative therapeutic target for the treatment of age-related diseases such as emphysema.